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Principal Investigator: Shabaana A. Khader
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2019
Award: $408,644
Funding agency: National Heart Lung and Blood Institute
DESCRIPTION (provided by applicant): Approximately one-third of the world's population is latently infected with Mycobacterium tuberculosis (Mtb) with a 10% risk of developing pulmonary tuberculosis (TB) over their lifetime. Global efforts to combat TB are hampered by the emergence of drug-resistant strains of Mtb and variable efficacy of the currently available vaccine, M. bovis BCG (BCG). Thus, the development of an effective vaccine is critical for the elimination of TB as a public health problem. Studies in the past decade have mainly utilized induction of T helper 1 (Th1) responses and production of interferon gamma (IFNγ) as readouts for vaccine efficacy against TB. However, despite inducing high levels of IFN-γ, MVA85A, the first recombinant TB vaccine tested in human clinical trials, failed to protect against TB disease.
These data highlight the importance of exploring new approaches to improve vaccine-induced immunity against TB. During the prior funding period, we demonstrated that T helper type 17 (Th17) cells, which produce the cytokine interleukin-17 (IL-17), are the primary effector cell mediating vaccine-induced protection against Mtb. Although IFNγ is dispensable for vaccine-induced immunity against TB, IL-17 production by vaccine-induced Th17 cells is absolutely necessary to confer vaccine-induced protection against TB. Importantly, mucosal vaccination with the Mtb antigen in adjuvant induced potent lung-resident Th17 cells and improved BCG vaccine-induced protection following Mtb challenge. Our mechanistic studies showed that IL-17 induced chemokines, including CXCL-13, to localize CXCR5-expressing T cells near Mtb-infected macrophages, resulting in the formation of lymphoid follicles and activating macrophages to mediate Mtb control. Despite these major advances in understanding the role of Th17 vaccine-induced cells in TB, the accumulation of vaccine-induced Th17 recall responses in the lung is not accelerated enough to provide sterilizing immunity to Mtb infection. However, we show that vaccine-induced Th17 immunity can be harnessed using DC therapy to achieve near sterilizing immunity against Mtb challenge. Thus, in this renewal, in Aim 1, we will first determine if accelerating Th17 cell accumulation by modulating antigen-presenting cell (APC) function will improve Mtb control. In Aim 2, we will address the functional role of IL-17 in DC therapy in vaccinated mice, and the relationship between a Single Nucleotide Polymorphism (SNP) in the IL-17 promoter and vaccine-induced responses in humans. Finally, in Aim 3, we will identify and incorporate potent Th17- inducing adjuvants into protective mucosal TB vaccines to translate for future use in humans. These objectives will be addressed using novel Mtb T-cell receptor (TCR) transgenic (Tg) mouse models in combination with gene-deficient mice, mouse models of Mtb infection, novel adjuvants and vaccination strategies, and hypothesis testing in humans. The work proposed in this grant will allow us to promote Th17 responses to generate long-lasting vaccine-induced immunity against TB.
Terms: <Address><Adjuvant><Ammonium><Antigen-Presenting Cells><BCG Vaccine><BCG immunization><BCG treatment><BCG vaccination><BCG-vaccinated><BLR1><BLR1 gene><Bacille Calmette Guerin vaccine><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacillus Calmette Guerin Vaccine><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Bacillus Calmette-Guérin vaccine><CTLA-8><CTLA8><CXCR-5><CXCR5><Cell Body><Cell Function><Cell Process><Cell Therapy><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Chemotactic Cytokines><Chitosan><Clinical Trials><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Data><Death><Dendritic Cell Therapy><Dendritic Cells><Development><Disease><Disorder><Drug Resistance Tuberculosis><Drug Resistant TB><Drug Resistant Tuberculosis><Drug resistance><Drug resistance in Mtb><Drug resistance in Mycobacterium Tuberculosis><Drug resistance in tuberculosis><Drug resistant M Tuberculosis><Drug resistant Mtb><Drug resistant Mycobacteria Tuberculosis><Effector Cell><Enterotoxins><Funding><Future><Gamma interferon><Genes><Goals><Grant><Homologous Chemotactic Cytokines><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><IL-17><IL-17A><IL-23><IL17 Protein><IL17A><Immune Interferon><Immune response><Immunity><Immunological response><Incidence><Intercrines><Interferon Gamma><Interferon Type II><Interferon-gamma><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 Precursor><Interleukin-17><Lipid A><Lung><Lung Respiratory System><Lung TB><Lung Tuberculosis><Lymphoid Follicle><M bovis><M tb><M tuberculosis><M tuberculosis infection><M. bovis><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb><M.tb infection><M.tuberculosis><M.tuberculosis infection><MDR15><MHC Receptor><MTB infection><MTB vaccine><Macrophage Activation><Major Histocompatibility Complex Receptor><Mediating><Mice><Mice Mammals><Modern Man><Mtb drug resistance><Mucosa><Mucosal Tissue><Mucous Membrane><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Mycobacterium bovis><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis antigens><Mycobacterium tuberculosis infection><Mycobacterium tuberculosis var. bovis><Organism><Poliglusam><Population><Predisposition><Production><Public Health><Pulmonary TB><Pulmonary Tuberculosis><Receptors, Antigen, T-Cell><Recombinants><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Risk><Role><SIS cytokines><Salts><Single Base Polymorphism><Single Nucleotide Polymorphism><Subcellular Process><Susceptibility><T-Cell Receptor><T-Cells><T-Lymphocyte><TB drug resistance><TB infection><TB vaccine><Testing><Transgenic Mice><Translating><Tuberculosis><Tuberculosis Vaccines><Vaccinated><Vaccine Production><Vaccines><Veiled Cells><Work><accessory cell><anti-TB vaccine><base><cell mediated therapies><cell-based therapy><chemoattractant cytokine><chemokine><combat><cytokine><design><designing><develop a vaccine><development of a vaccine><developmental><disseminated TB><disseminated tuberculosis><drug resistance M Tuberculosis><drug resistance Mycobacteria Tuberculosis><drug resistant><drug resistant M.tb><drug resistant in tuberculosis><extensive drug resistance><extensively drug resistant><extreme drug resistance><host response><immunoresponse><improved><infection due to Mycobacterium tuberculosis><interleukin-23><intravesical BCG><lFN-Gamma><lipophilicity><living system><macrophage><mouse model><mtb><mucosal vaccination><multi-drug resistant><multidrug resistant><murine model><nano emulsion><nano particle><nano-sized particle><nanoemulsion><nanoparticle><nanosized particle><new approaches><novel><novel approaches><novel strategies><novel strategy><promoter><promotor><public health relevance><pulmonary><resistance strain><resistance to Drug><resistant strain><resistant to Drug><response><social role><thymus derived lymphocyte><tuberculosis infection><tuberculous spondyloarthropathy><vaccination strategy><vaccine development><vaccine efficacy><vaccine evaluation><vaccine formulation><vaccine screening><vaccine testing><vaccine-induced immunity><vaccine-induced protection>